A Aronova (1), F Tosato (1), N Naser (1), D Correa-Gallegos (1), M Georgakis (1), N Beaufort (1), SW van der Laan (2), B Wefers (3), L Strohm (3), M Brandhofer (1), C Behrends (3), I Forne (4), S Lahiri (4), A Imhof (4), S Steffens (5), J Bernhagen (1), Y Asare (1) *, M Dichgans (1) *

1. Institute for Stroke and Dementia Research, LMU Munich, Munich, Germany; 2. University Medical Center Utrecht, University of Utrecht, the Netherlands; 3. Deutsches Zentrum für Neurodegenerative Erkrankungen e. V. (DZNE), LMU Munich, Munich, Germany; 4. Protein Analysis Unit, Faculty of Medicine, Biomedical Center, LMU, Martinsried, Germany; 5. Institute for Cardiovascular Prevention (IPEK), LMU Munich, Munich, Germany

* Equal senior contribution

Background: Scavenger receptor-mediated LDL retention, endothelial transcytosis, and foam cell formation drive the initiation of atherosclerosis. SCARF1 (scavenger receptor class F member 1) binds carbamylated and acetylated LDL, and recognizes apoptotic cells. Its unusually long cytoplasmic tail implies involvement in intracellular signaling. Genetic variants at the SCARF1 locus are associated with ischemic stroke, particularly with large artery atherosclerosis. However, role of SCARF1 in atherosclerosis remains unexplored.

Methods and Results: To investigate the role of SCARF1 in atherosclerosis, we analyzed spontaneous atherosclerotic plaque formation in 28-week-old mice on chow diet. Scarf1 deficiency was atheroprotective with fewer advanced plaques, reduced necrotic core expansion and downregulated release of pro-inflammatory Cxcl1 and Ccl2. SCARF1 bound oxLDL with higher affinity than nLDL, promoting foam cell formation. Single-cell RNA sequencing data from human and mouse atherosclerotic plaques revealed SCARF1 is predominantly expressed in endothelial cells (ECs) and upregulated by atherogenic diet. Proteomicprofiling of ECs showed downregulation of ERK-MAPK pathway upon Scarf1 depletion. Likewise, phosphoproteomics revealed alterations in MAPK-related phosphosites. Scarf1 deficiency reduced ERK1/2 phosphorylation upon oxLDL stimulation, whereas SCARF1 overexpression enhanced it. SCARF1 physically interacted with GRB2, a key adaptor protein for ERK-MAPK activation; deletion of SCARF1’s cytoplasmic tail abolished this interaction. In human carotid plaques, SCARF1 expression correlated with plaque instability, including large lipid core, reduced collagen content, and elevated MMP8/MMP9 activity.

Conclusion: Our results show a dual function of SCARF1 as a signaling receptor and lipid transporter linking inflammation with lipid metabolism. Its therapeutic inhibition could offer a promising strategy for treating atherosclerosis.